Isonicotinyl hydrazone of m-formyl-benzene sulfonic acid



United States Patent ISONICOTINYL HYDRAZONE 0F M-FORNIYL- BENZENE SULFONIC ACID Andr Girard, Paris, France, assignor to Les Laboratoires Francais De Chimiotherapie, Paris, France, a French body corporate No Drawing. Application November 19, 1953, Serial No. 393,241

Claims priority, application France November 24, 1952 Claims. (Cl. 260-295) are known. Said known compounds exhibit a bacteriostatic activity of about the same order as said isonicotinic acid hydrazide. Heretofore, it was, however, not possible to ascertain whether said activity was solely due to the liberation of isonicotinic acid hydrazide itself in the course of hydrolytic processes taking place in the culture medum or in the animal organism itself.

All the known compounds of said isonicotinic acid hydrazone series are actually quite toxic and, therefore, cannot be utilized and administered in the dosage required for therapeutic application.

It is one object of this invention to provide a new isonicotinic acid hydrazone compound which has a remarkably high bacteriostatic activity especially against Mycobacterium tuberculosis and'the toxicity of which, at the same time, is extremely low and, thus, clearly distinguishes said compound over any other member of said series of compounds.

Another object of this invention is to provide salts of said new isonicotinic acid hydrazone, which salts are soluble in water and, therefore, are suitable for parenteral administration.

A further object of this invention is to provide a simple and effective process of producing said new isonicotinic acid hydrazone compound and its salts, said process allowing the production of said compound and its salts in a high yield and of a high degree of purity.

Other objects of this invention and advantageous features thereof will become apparent as the description proceeds.

The new isonicotinic acid hydrazone according to the present invention is the isonicotinic acid hydrazone of benzaldehyde-m-sulfonic acid of the following formula This hydrazone has proved to be far superior to any of the other known hydrazones and to its isomers and homologues in its pharmacological properties and its therapeutical applicability. Its chemotherapeutic activity in experimental tubercular infections exceeds that of any of the compounds described heretofore.

While the sodium salt of said acid is well tolerated for 15 days when administered in a daily dose of 50 mg. per mouse of 20 g., i. e., in an amount of 2.6 g. per kg. when given perorally and in an amount of 1 g. per kg. when given by quick intravenous injection it exhibits an activity completely suppressing experimental infections of said animals in a dose of 0.1 mg. per animal When given per 03 during 50 days of treatment. These figures correspond to a chemotherapeutic index, i. e., the ratio between minimum curative dose and maximum tolerated dose of 1:500. Such a coefiicient is higher than any heretofore observed.

Administration of a daily dose of several grams of said compound to humans has been tolerated without any side-effects.

The new acid is a microcrystalline, yellowish-white compound which is very slightly soluble in water and does not have a definite melting point. It is readily soluble in solutions of basic compounds yielding therewith well crystallizing neutral salts which are moderately soluble in Water and generally insoluble in alcohol.

Due to the presence of acid and basic functional groups in said new hydrazone compound, the free acid itself is of weakly acid reaction. Therefore, acetic acid in excess is capable of replacing it in and setting it free from its salts. Like sulfanilic acid, it is practically insoluble in dilute mineral acids.

At the moment it is precipitated by acids from solutions of its alkali metal salts, it is almost white; but it becomes slightly yellowish on prolonged contact with air.

Its alkali metal salts, on the other hand, are not changed by such contact with air and are stable to sterilization.

The sodium salt crystallizes in fine white felted needles. Said salt contains three mols of water of crystallization, l g. thereof being soluble in 33 cc. of water at 18 C. and being very readily soluble at elevated temperatures.

The ammonium salt crystallizes in the form of white needles, 1 part of which being soluble at 18 C. in 11 parts of water. The lithium salt dissolves in 10 parts of cold water.

The diethylamino ethanol salt is especially suitable for parenteral administration because it is very soluble in water.

The new hydrazone acid and its salts are obtained, according to the process of this invention, by condensing isonicotinic acid hydrazide with benzaldehyde-m-sulfonic acid and, if desired, converting the resulting sulfonic acid into its salts.

The condensation is carried out in aqueous neutral or acid medium.

It is also possible to produce the new acid by first sulfonating benzaldehyde to form benzaldehyde-m-sulfonic acid and directly adding isonicotinic acid hydrazide to the reaction mixture after diluting the same to reduce its acidity.

The following examples serve to illustrate the present invention Without, however, limiting the same thereto.

Example 1 1 kg. of oleum containing 35% of sulfur trioxide are placed into a 3 liter flask provided with a stirring device and a thermometer. 212 g. (2 mol) of freshly distilled benzaldehyde are added drop by drop thereto Without cooling and while thoroughly stirring. The temperature at the end of the reaction is about -65 C.

The reaction mixture is then heated on a boiling water bath for IOminutes.

After cooling, the mixture is slowly poured into a vessel containing 3 kg. of crushed ice.

The small amount of unreacted benzaldehyde present in said mixture is removed by distillation of the aqueous solution until about 400' cc. of distillate are obtained;

The cooled solution is diluted with about an' equal volume of water whereby its final volume amountsto 8 liters. sponds to a 3 N acid solution. 200 g. of isonicotinic acid hydrazide, which previously had been dissolved in one liter of lukewarm water, are added to said solution.

The hydrazone precipitates immediately; It is filtered off and is well Washed with water until all the sulfuric acid is eliminated. Finally it is Washed with 500 cc; of 90% alcohol.

The resulting i sonic'otini'c' acid hydrazone of benzaldehyde-m-sulfonic acid is dried on a waterbath. The yield calculated for the ii' 'drazid'e' em loyed in this reaction is practically quantitative.

Example 2 filtered, washed with 400 cc. of absolute alcohol, and q air-dried. 315 g. of the snow-White sodium salt are obtained. Said salt crystallizes with 3 mols of water.

A small amount of the hydrazone acid is recovered by acidifying the mother liquors.

Other salts of said hydrazone acid are obtained by proceeding in a similar manner.

0 course, many other changes and variations in the condensation conditions, the reaction temperature and duration, the methods of separating the hydrazone acid from the reaction mixture and of purifyingthe same, the methods of producing its salts, and thelike', may be made by those skilled in the art in accordance with the principles set forth herein and in the claims annexed hereto.

I claim:

1. The isonicotinic acid hydrazone of benz'aldehydem'-sulfonic acid of the following formula 2. The sodium salt of the isonicotinic acid hydrazone of benzaldehyde-m-sulfonic acid.

The concentration of the dilute solution co'rre- 3. The ammonium salt of the isonicotinic acid hydrazone of benzaldehyde m-sulfonic acid.

4. The lithium salt of the isonicotinic acid hydrazone of benzaldehyde-m-sulfonic' acid.

5. The diethylamino ethanol salt of the isom'cotinic acid hydrazone of benzal'rfehyde m-sulfonic acid.

6. An isonicotinie acid hydrazone compound of benzaldehyde-m-sulfonic acid selected" from the group consisting of the isonicotinic acid hydrazone of benzaldehyde m sulfonic acid of the following" formula acid hydrazone ofbenz'aldeiiyde msulfonie acid, the steps comprising condensing isonico'tinie acid hydrazide with benzaldehyde-m-sulfonic acid' in an a ueous, non-alkaline medium and converting the resulting hydrazone into its salts of metals and organicbases, said salt's-beingcompatible to the human body.

9. In a process of producing the isonicotinic acid hydrazone of benzaldehyde-m-stllfonic acid, the steps comprising adding to a solution of benzaldehyde-m-sulionic acid in about 3 N sulfuric acid isonicotinic acid hydrazide dissolved in lukewarm water, filtering off the precipitated hydrazone, and washing said hydrazone until it is completely free of sulfuric acid.

10. In a process ofproducing a salt of the isonicotinic acid hydrazone of benzaldehyde-msulfonic acid, the steps comprising dissolving the isonicotinic acid hydrazone of benzaldehyde-m-sulfonic acid in an equimolecular amount of an aqueous solution of a base selected from the group consisting of ammonium, a' metal, and an organic base, said base fornjingfa salt with said hydrazone, said salt being compatible to the human body while heating and causing the salt to crystallize from the reaction mixture.

References Cited in the file of this patent Bavin et al.: J; Pharm. and PharmacoL, vol. 4,- #11, pp. 844-54 (1952),- (TableI Oompound#192) page 851. 

6. AN ISONICOTINIC ACID HYDRAZONE COMPOUND OF BENZALDEHYDE-M-SULFONIC ACID SELECTED FROM THE GROUP CONSISTING OF THE ISONICOTINIC ACID HYDRAZONE OF BENZALDEHYDE-M-SULFONIC ACID OF THE FOLLWING FORMULA
 10. IN A PROCESS OF PRODUCING A SALT OF THE ISONICOTINIC ACID HYDRAZONE OF BENZALDEHYDDE-M-SULFONIC ACID, THE STEPS COMPRISING DISSOLVING THE ISONICOTINIC ACID HYDRAZONE OF BENZALDEHYDE-M-SULFONIC ACID IN A EQUIMOLECULAR AMOUNT OF AN AQUEOUS SOLUTION OF A BASE SELECTED FROM THE GROUP CONSISTING OF AMMONIUM, A METAL, AND AN ORGANIC BASE, SAID FORMING A SALT WITH SAID HYDRAZONE, SAID SALT BEING COMPATIBLE TO THE HUMAN BODY WHILE HEATING AND CAUSING THE SALT TO CRYSTALLIZE FROM THE REACTION MIXTURE. 